title: Bile proteomic profiles differentiate cholangiocarcinoma from primary sclerosing cholangitis and choledocholithiasis.
abstract: Early detection of malignant biliary tract diseases, especially cholangiocarcinoma (CC) in patients with primary sclerosing cholangitis (PSC), is very difficult and often comes too late to give the patient a therapeutic benefit. We hypothesize that bile proteomic analysis distinguishes CC from nonmalignant lesions. We used capillary electrophoresis mass spectrometry (CE-MS) to identify disease-specific peptide patterns in patients with choledocholithiasis (n = 16), PSC (n = 18), and CC (n = 16) in a training set. A model for differentiation of choledocholithiasis from PSC and CC (PSC/CC model) and another model distinguishing CC from PSC (CC model) were subsequently validated in independent cohorts (choledocholithiasis [n = 14], PSC [n = 18] and CC [n = 25]). Peptides were characterized by sequencing. Application of the PSC/CC model in the independent test cohort resulted in correct exclusion of 12/14 bile samples from patients with choledocholithiasis and identification of 40/43 patients with PSC or CC (86% specificity, 93% sensitivity). The corresponding receiver operating characteristic (ROC) analysis revealed an area under the curve (AUC) of 0.93 (95% confidence interval [CI]: 0.82-0.98, P = 0.0001). The CC model succeeded in an accurate detection of 14/18 bile samples from patients with PSC and 21/25 samples with CC (78% specificity, 84% sensitivity) in the independent cohort, resulting in an AUC value of 0.87 (95% CI: 0.73-0.95, P = 0.0001) in ROC analysis. Eight out of 10 samples of patients with CC complicating PSC were identified.
  
  
  CONCLUSIONS
  Bile proteomic analysis discriminates benign conditions from CC accurately. This method may become a diagnostic tool in future as it offers a new possibility to diagnose malignant bile duct disease and thus enables efficient therapy particularly in patients with PSC.
authors.affiliation: Department of Gastroenterology, Hepatology and Endocrinology, Hannover Medical School, Hannover, Germany. lankisch.tim@mh-hannover.de
authors.forename: Tim O
authors.initials: TO
authors.lastname: Lankisch
authors.forename: Jochen
authors.initials: J
authors.lastname: Metzger
authors.forename: Ahmed A
authors.initials: AA
authors.lastname: Negm
authors.forename: Katja
authors.initials: K
authors.lastname: Vosskuhl
authors.forename: Eric
authors.initials: E
authors.lastname: Schiffer
authors.forename: Justyna
authors.initials: J
authors.lastname: Siwy
authors.forename: Tobias J
authors.initials: TJ
authors.lastname: Weismüller
authors.forename: Andrea S
authors.initials: AS
authors.lastname: Schneider
authors.forename: Kathrin
authors.initials: K
authors.lastname: Thedieck
authors.forename: Ralf
authors.initials: R
authors.lastname: Baumeister
authors.forename: Petra
authors.initials: P
authors.lastname: Zürbig
authors.forename: Eva M
authors.initials: EM
authors.lastname: Weissinger
authors.forename: Michael P
authors.initials: MP
authors.lastname: Manns
authors.forename: Harald
authors.initials: H
authors.lastname: Mischak
authors.forename: Jochen
authors.initials: J
authors.lastname: Wedemeyer
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001646:Bile / Q000737:chemistry*; D018281:Cholangiocarcinoma / Q000175:diagnosis*; D015209:Cholangitis, Sclerosing / Q000175:diagnosis; D042883:Choledocholithiasis / Q000175:diagnosis*; D019075:Electrophoresis, Capillary; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D008297:Male; D013058:Mass Spectrometry; D008875:Middle Aged; D020543:Proteome / Q000032:analysis*
chemical_list: D020543:Proteome